Xu et al. BMC Medical Genetics(2020) 21:239
https://doi.org/10.1186/s12881-020-01164-1

CASE REPORTOpen Access

DGAT1 mutations leading to delayed
chronic diarrhoea: a case report
Luojia Xu1, Weizhong Gu2, Youyou Luo1, Jingan Lou1 and Jie Chen1*

Abstract
Background: Early-onset chronic diarrhoea often indicates a congenital disorder. Mutation in diacylglycerol oacyltransferase 1 (DGAT1) has recently been linked to early-onset chronic diarrhoea. To date, only a few cases of
DGAT1 deficiency have been reported. Diarrhoea in those cases was severe and developed in the neonatal period
or within 2 months after birth.
Case presentation: Here, we report a female patient with DGAT1 mutations with delayed-onset chronic diarrhoea.
The patient had vomiting, hypoalbuminemia, hypertriglyceridemia, and failure to thrive at early infancy. Her
intractable chronic diarrhoea occurred until she was 8 months of age. A compound heterozygous DGAT1 mutation
was found in the patient, which was first found in the Chinese population. Her symptoms and nutrition status
improved after nutritional therapy, including a fat restriction diet.
Conclusions: This case expanded our knowledge of the clinical features of patients with DGAT1 mutations.
Intractable diarrhoea with delayed onset could also be a congenital disorder.
Keywords: Infantile diarrhoea, Failure to thrive, Genetics, Diacylglycerol o-acyltransferase, Case report

Background
Chronic diarrhoea is defined as diarrhoea lasting longer
than 2 weeks [1]. The aetiology of chronic diarrhoea varies[1]. A group of chronic diarrhoea disorders may occur inearly infancy and can be termed “congenital diarrhoea”[1]. Many patients with disorders in this group are affectedby monogenic disorders that primarily affect the intestinal
epithelium or secondarily affect intestinal epithelial function [1]. With the increasing use of next-generation sequencing in clinical practice, many monogenic disordersthat cause chronic diarrhoea have been revealed. One ofthese monogenic disorders is caused by a mutation in the
diacylglycerol o-acyltransferase 1 (DGAT1) gene (MIM #:604900). The DGAT1 gene encodes diacylglycerol o* Correspondence: 6185020@zju.edu.cn
1
Present Address: Department of Gastroenterology, Children’s Hospital,
Zhejiang University School of Medicine, National Clinical Research Center forChild Health, No.3333, Binsheng Road, Hangzhou, Zhejiang Province, PR
China
Full list of author information is available at the end of the article

acyltransferase 1 (DGAT1), which is a microsomal enzyme
with high expression in the small intestine, adrenal cortex,
adrenal medulla, and testes [2]. DGAT1 and its isozyme
DGAT2 catalyse the final step in triglyceride (TG) synthesis by using diacylglycerol (DAG) and fatty acyl CoA in
humans [3] and help to absorb TGs in the small intestine[2]. However, in humans, only DGAT1 is highly expressedin the intestine [4].
Recent studies have shown that DGAT1 mutation islinked to chronic and severe diarrhoea that mostly develops in the neonatal period [4–7] or within 2 months
after birth [7, 8]. Herein, we report a female patient who
had delayed-onset chronic diarrhoea with a compound
heterozygous DGAT1 mutation, which, to our knowledge, has not been previously reported.

Case presentation
The patient was a girl born at 41 weeks gestation withspontaneous labour. Her birth weight was 3.3 kg, andher length was 51.0 cm. Her mother denied any prenatal© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.

Xu et al. BMC Medical Genetics(2020) 21:239

events. She came from a non-consanguineous Chinesefamily, and she was the first child without any siblings.
She presented vomiting soon after birth but with normalstool output. The physical examination showed dehydration, but the rest of the examination was unremarkable.
Her serum albumin and TG were in the normal range
when she was 22 days old. She presented recurrent hypoalbuminemia and hypertriglyceridemia with a serum
TG level of 8.34 mmol/L (normal range is < 1.70 mmol/L) and normal cholesterol since she was 34 days old. She
began to have several episodes of watery diarrhoea daily
when she was 8 months old. She was breastfed after
birth and then changed to an amino acid-based formulaor extensively hydrolysed-based formula because of asuspected cow’s milk protein allergy. Her routine stool
test was normal, with negative results for viruses, bacteria, or parasites. In other laboratory results, immunoglobins decreased (IgG 0.96 g/L, IgA 0.15 g/L, IgM 0.32g/L), and abnormalities were also revealed in the T and
B cell subset analysis (CD20 14.22%, CD3 65.44%, CD4
20.56%, CD8 34.90%, NK cell 6.55%, CD4/CD8 0.59).
Prealbumin and IgE levels were unremarkable most of
the time. Her iron level was 5.51 mmol/L (normal range
6.63–11.82 mmol/L), which was slightly low, but zinc,magnesium, and copper levels were all within a normal
range. Retinol-binding protein was lower at 19.40 mg/L
(normal range: 22–53 mg/L), while vitamin D, vitamin
B12, and folic acid levels were normal. Insulin-likegrowth factor-1 (IGF-1) was < 25.0 ng/ml (normal range
51.0–303.0 ng/ml), and insulin-like growth factor binding protein-3 (IGFBP-3) was 0.7 μg/ml (normal range
0.8–3.9 μg/ml). The upper gastrointestinal contrast study
showed nothing but a gastroesophageal reflex. Oesophagogastroduodenoscopy with biopsy was performed,
which showed slightly flat villi in the descending duodenum, and pathology results demonstrated slight inflammation at the gastric antrum mucosa and chronicmucosal inflammation in the descending part of theduodenum. A percutaneous endoscopic gastrostomy anda percutaneous endoscopic transgastric jejunostomy
were performed during the whole treatment course. She
was given either an amino acid-based formula or extensively hydrolysed-based formula using gastrostomy tube
feeding or jejunal tube feeding. Because of poor feedingwith ongoing loss from the gastrointestinal tract, parenteral nutrition was added. She was on parenteral nutrition for approximately 11 months with an interruption
for catheter-related infection, thrombosis, or discharge
against doctor’s orders. She had several episodes ofbacterial or viral infections. Her parenteral nutrition provided a total energy of 71.4–153.5 kcal/kg daily with anamino acid supply of 2.5–3.5 g/kg daily, and she could
tolerate a maximum dose of 3.8 g/kg/d lipid emulsion(including 2.0 g/kg/d medium-chain triglyceride/long-

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chain triglyceride fat emulsion and 1.8 g/kg/d ω-3 fishoil lipid emulsion) without TG elevation or parenteralnutrition-associated cholestasis. She also received albumin, intravenous immune globulin infusion, and red
blood cell transfusion when moderate anaemia occurred.
When her feeding volume was decreased or she was put
on nothing by mouth, her symptoms improved temporarily, and vice versa. Even then, she still suffered from a
failure to thrive during hospitalization. Weight-for-age
z-score (WAZ), length/height-for-age z-score (HAZ) andweight-for-length z-score (WHZ) were calculated by
WHO Anthro software (version 3.2.2). Her WAZ and
WHZ were always below -3. She was accidentally fed
with rice porridge for a couple of days, and her symptoms were relieved when she was 16 months old. Afterher parents provided the consents, the whole-exome sequencing (WES) of peripheral blood from the proband
was performed, and the Sanger sequencing was performed with her parents’ peripheral blood to confirm
whether they had the same mutations as the proband.
WES was performed as described previously [9]. The
analysis results showed that our patient had compound
heterozygous mutations in DGAT1: a paternally inherited splicing mutation at chr8: 145541376 c.895-1G > A
and a maternally inherited splicing mutation at chr8:145541757 c.751 + 1G > C. The Sanger sequencing results are shown in Fig. 1. Her father and mother were
heterozygous for each mutation.
The two mutations were both splicing mutations andcould affect the results of transcription and translation.
The analysis from the gnomAD database (gnomad.
broadinstitute.org) showed that the mutation at chr8:145541376, c.895-1G > A was only reported in nonFinnish European populations with 1/251026 in total
allele counts [10]. The other mutation was not previously reported in the gnomAD database. Use of GERP++[11] suggested that the mutations were conserved. In
addition, use of MutationTaster (http://www.mutationtaster.org) [12] to test the potential pathogenicity of thesemutations revealed that they were disease-causing. Human Splicing Finder (http://www.umd.be/HSF/) [13]showed that these two mutations most likely affected
splicing.
DGAT1 protein expression in enterocytes was assessedby immunohistochemistry (IHC) staining in the biopsy
tissue. IHC processing followed the instructions and is
described in Additional file 1. DGAT1 protein expression in the gastric antrum (Fig. 2a) and duodenum (Fig.
2b and c) of the proband was shown in Fig. 2. Additional
figures of the IHC results in the duodenum can be seenin Additional file 2.
The proband was confirmed with a diagnosis of
DGAT1 deficiency. As a result, she moved to a fatrestricted diet. She started with rice porridge and rice

Xu et al. BMC Medical Genetics(2020) 21:239

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Fig. 1 Sanger sequencing results show mutations in DGAT1 detected in the proband’s family. a Chromatogram showing the proband with aheterozygous mutation at chr8:145541376, c.895-1G > A. b Chromatogram showing the proband’s father carrying the same heterozygous
mutation, c.895-1G > A. c Chromatogram showing the proband’s mother with no mutation at this site. d Chromatogram showing the proband
with another heterozygous mutation at chr8:145541757, c.751 + 1G > C. e Chromatogram showing the proband’s father with no mutation at thissite. f Chromatogram showing the proband’s mother carrying the same heterozygous mutation, c.751 + 1G > C

cereal, which were mainly carbohydrates. Lean meat andvegetables were introduced later as complementary
feeding of semisolid foods. She did well without diarrhoea or vomiting. Finally, she was weaned off parenteralnutrition. She was 4 years and 2 months old at the lastvisit in the outpatient clinic, and she had an improved
nutrition status (body weight 14.4 kg, height 95.0 cm,

WAZ -0.92, WHZ 0.40, HAZ -1.97) with no signs ofsymptom recurrence. The pedigree of the proband’sfamily was shown in Fig. 3a. The growth curve wasshown in Fig. 3b, Fig. 3c, and Fig. 3d. Albumin andimmunoglobins remained in the normal range without
the requirement of extra infusion. She had a normal TG
level under a fat-restricted diet. IGF-1 and IGF BP-3 also

Fig. 2 DGAT1 protein expression in the proband. a Immunohistochemistry of DGAT1 in the proband’s biopsy of the gastric antrum (× 100). b
Immunohistochemistry of DGAT1 in the proband’s biopsy at the duodenum (× 100). c Immunohistochemistry of DGAT1 in the proband’s biopsy
at the duodenum (× 200)

Xu et al. BMC Medical Genetics(2020) 21:239

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Fig. 3 Pedigree of the proband’s family and the growth curve of the proband. a Pedigree of the affected family. The proband is indicated with ablack arrow; it could be an autosomal recessive disease. b WAZ of the proband’s growth parameters. c HAZ of the proband’s growth parameters.
d WHZ of the proband’s growth parameters. Short black arrows indicate the time when the proband received parenteral nutrition, and the redarrows indicate the time point when the proband started a fat-restricted dietreturned to the normal range. Her parents were satisfied
with this result.

Discussion and conclusions
Fat is the main energy source for infants, and lipid
metabolism widely exists in the human body, not only in
different systems but also in different kinds of cells.
DGAT1 plays an important role in TG synthesis [3].
Thus, theoretically, mutations in DGAT1 can cause
variant symptoms not only related to lipid absorption
but also related to dysfunction of multiple organs.
Human intestines may be more sensitive to DGAT1
mutations because of the lack of expression of DGAT2[4]. Recent studies [4–8, 14] (Table 1) showed mutationsin DGAT1 from a total of 23 patients are linked to PLEwith failure to thrive. These studies revealed that
DGAT1 mutations can lead to early-onset, chronic andintractable diarrhoea, which may develop into intestinal
failure. In contrast with previously reported cases, ourpatient had diarrhoea until 8 months after birth despite
her hypertriglyceridemia occurring in early infancy. Thismight have contributed to her compound heterozygous
mutations in DGAT1. Another important symptom ofpatients with DGAT1 mutations is vomiting. Our patientalso had vomiting, which was similar to the reported 12
patients [4, 7, 8]. A previous study [15] may explain thepotential reason: intestinal DGAT1 deficiency inhibits
chylomicron secretion and delays gastric emptying.
Other clinical characteristics that our patient had, suchas failure to thrive, hypoalbuminemia, and decreased
serum immunoglobins, have also described in previous
studies [4–8].
Mutations in DGAT1 leading to protein expression deletion or downregulation are still controversial. One
study [7] revealed that some DGAT1 mutations cancause a lack of DGAT1 protein expression in the humanepithelial cells of the duodenum, ileum, colon, patientderived fibroblasts, Epstein-Barr virus-derived Blymphoblastic cell lines and patient-derived intestinalorganoids. In addition, another two studies [5, 6] revealed that some mutations in DGAT1 can cause partial
function loss, which leads to decreased expression in patients’ dermal fibroblasts. The differences may be due tothe different locations of the mutation in the DGAT1
gene. Further functional analysis of mutated alleles isneeded to obtain a better understanding of the
genotype-phenotype relationships in DGAT1 mutation
patients.
The DGAT1 mutations in our patient were two compound mutational sites in the DGAT1 exon region,
which were located in splice sites and probably affected
the function of the protein. They were likely pathogenic.

Xu et al. BMC Medical Genetics(2020) 21:239

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Table 1 Characteristics of published DGAT1 deficiency patients
Patient Descent

Onset
age

Features

Nutrition support

Other Treatment

OutcomePatient
1 [4]Ashkenazi
Jewish0.1
monthvomiting, diarrhoea, malnutrition,
hypertriglyceridemia, hypoalbuminemia

TPN, gastrostomy tube feedingwith amino acid-based formula

albumin infusion

died

Patient
2 [4]Ashkenazi
Jewish0.1
monthdiarrhoea, hypertriglyceridemia,
hypoalbuminemia

TPN and amino acid-based formula feedingalbumin infusion,cholestyramin

thrived at 46 months of age on
an unrestricted diet

Patient
3 [5]ArabMuslim

2monthsdiarrhoea, extremity edema, cachectic
with FTT, hypertriglyceridemia,
hypoalbuminemia

amino acid-based formula feed- albumin and IVIG
ing, later with PN and Monogen infusion, metronidazole
formulainfusiondischarged home without
diarrhoea

Patient
4 [5]ArabMuslim

NM

diarrhoea, edema, weight loss and skinabscesses

NM

NM

died

Patient
5 [5]Ashkenazi
Jewish0.27
monthsdiarrhoea, FTT, edema, hypotonia

TPN and amino acid-based formula feeding

chicken soup formulamixed with rice waterand ORS

improved on a regular dietexcept for dairy productsPatient
6 [5]Ashkenazi
Jewishsoonerafter
birth

diarrhoea, hypertriglyceridemia

TPN

chicken soup formulamixed with rice waterand ORS

maintained his weight albuminon enteral feeding

Patient
7 [5]

NM

NM

NM

NM

NM

NM

Patient
8 [5]

NM

NM

NM

NM

NM

NM

Patient
9 [6]

South
Asian

shortly
after
birth

diarrhoea, FTT, hypertriglyceridemia

PN, gastrostomy tube feedingwith a hydrolyzed formula

blood cell transfusion,
IVIG

transitioned to a diet containing
no more than 10% calories fromfat

Patient
10 [6]

South
Asian

shortly
after
birth

diarrhoea

NMNM

improved on a very low fat
enteral diet.

Patient
11 [7]

Turkishbirthvomiting, diarrhoea, FTT,
hypoalbuminemia

Fat-free fomula and MCT

albumin infusion

no diarrhoea and normal growthwith low-fat diet +MCT + fat-freeformulaPatient
12 [7]

Turkishbirthvomiting, diarrhoea, FTT,
hypoalbuminemia

NMalbumin infusion

died

Patient
13 [7]

Turkish0.75
monthsvomiting, diarrhoea, FTT,
hypertriglyceridemia, hypoalbuminemia

TPN

albumin infusion

diarrhoea improved with basic
formula feeding

Patient
14 [7]

Turkish2
monthsvomiting, diarrhoea, FTT,
hypoalbuminemiaNMcholestyramine

diarrhoea improved

Patient
15 [7]

Turkish1.3
monthsvomiting, diarrhoea, FTT,
hypoalbuminemia

hydrolyzed formula

Creon pancreatic lipase

diarrhoea improved but
remained malnutrition

Patient
16 [7]

Turkish2.5
monthsvomiting, diarrhoea, FTTNMCreon pancreatic lipase

diarrhoea improved

Patient
17 [7]

Caucasian1
monthvomiting

infusion of Intralipid andOmegaven suppletion of lipid
soluble vitamins

NMenteral feeding without fat

Patient
18 [7]

Caucasian1
monthvomiting, FTT

infusion of Intralipid andOmegaven suppletion of lipid
soluble vitamins

NMenteral feeding without fat

Patient
19 [7]

Caucasianbirthvomiting, diarrhoea, FTT,
hypoalbuminemia

TPN

small boweltransplantation

still stunted

Patient
20 [7]

Caucasianbirthvomiting, diarrhoea, FTT,
hypoalbuminemia

TPN, fat-free formulaNMstill stunted

Patient
21 [8]

Caucasian1
monthvomiting, diarrhoea, malnutrition,
hypoalbuminemia

TPN, nasojejunal tube feedingwith amino acid-based formula

antibiotics

improved on a low-fat diet

Patient
22 [14]Chinesebirthvomiting, watery diarrhoea

TPN

albumin and IVIG
infusion

died

Patient
23 [14]Chinesebirthedema,watery diarrhoea

TPN, enteral nutrition

albumin and IVIG
infusion

died

TPN Total parenteral nutrition, PN Parenteral nutrition, IVIG Intravenous immune globulin, NM Not mentioned, FTT Failure to thrive, MCT Medium-chain triglyceride,
ORS Oral rehydration solution

The patient’s clinical characteristics and immunohistochemical results of the duodenum were also in line withthe pathogenicity of such compound heterozygous

mutations. To date, several homozygous mutations havealready been identified in Turkish Caucasians in the
Netherlands and South Asian, Ashkenazi Jew, Arab-Xu et al. BMC Medical Genetics(2020) 21:239

Muslim, and Chinese populations [4–7, 14]. There is
one case of compound heterozygous mutations in Caucasians [8]. This is the first described compound heterozygous mutation in the Chinese population.
How the variant mutations in DGAT1 are linked to such
critical disease remains unknown. One [7] of those studies
explored the possible molecular pathomechanism: lipotoxicity in the intestinal epithelium accompanied by
DGAT1 deficiency leads to mucosal injury, which developed clinical features of PLE. However, to date, those reported patients had variant onset ages of different
symptoms. Further investigation will be needed to explore
the deeper mechanism. Autophagy or endoplasmic
reticulum stress is also possibly involved in this process
and has already been implicated in other lipid metabolic
disorders [16].
For the early diagnosis of this disease, patients usuallyshow signs of PLE with failure to thrive in early infancy,
but delayed intractable diarrhoea is also one of the clinical characteristics. The faecal elastase level is not a specific indicator [7] but can be used to rule out someother diseases with similar symptoms. The faecal alpha1-antitrypsin level is helpful to establish the diagnosis of
PLE [17]. Although DGAT1 mutations affect lipid
metabolism, not all patients have hypertriglyceridemia[5–7]. Including our patient, 7 in 24 patients [5–8] werereported to have hypertriglyceridemia. Unexplained
hypertriglyceridemia in early life may be a strong indicator of lipid metabolic disorder. Patients always have a
failure to thrive with extremely poor nutrition status,
but prealbumin may be at a normal level as in our patient. In PLE patients, albumin synthesis increases while
enteric albumin is lost [18], and the body cannot
compensate completely [19]. Thus, proteins with longer
half-lives, such as albumin and immunoglobulins, are affected, but proteins with shorter half-lives, such as prealbumin, are less affected. In our patient, IGF-1 and
IGFBP-3 both decreased in the early clinical course andreversed to normal levels during the follow-up when her
nutrition status improved. This indicates that IGF-1 and
IGFBP-3 change secondary to malnutrition, which isconsistent with some previous findings [20, 21]. Most of
the patients [4, 5, 7], including our patient, have recurrent infections. This may be due to decreased immunoglobin levels secondary to malnutrition and long-term
use of central lines.
Nutrition therapy with a fat-restricted diet is an effective way to manage these patients. When reviewing dietchanges in 16 surviving patients, 9 patients showed agood response to a low-fat diet (Table 1). One of themtransitioned to a regular diet, and the remaining 8 patients were still on a low-fat diet [6–8]. One study [6] reported that the patient had a diet in which fat supplied
less than 10% calories. Our patient showed great

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improvement after a fat-restricted diet was introduced.
Since an analysis [22] says that approximately 95–98% ofbreast milk fat is TG, breastfeeding may not be a good
choice for babies with DGAT1 deficiency. The patientreported here also showed intolerance of breastfeeding.
Parenteral nutrition plays an important role even whenthe exact aetiology is unclear. When the genetic test andimmunohistochemical results confirm the diagnosis, thetransition to a fat-restricted diet will still need parental
nutrition to provide essential fatty acids and fat-soluble
vitamins. Thus, occasional infusion of lipid emulsion
with fat-soluble vitamins is necessary [7]. In our experience, early intervention with parenteral nutrition prevents fat-soluble vitamin deficiency despite the unclear
aetiology. Our patient tolerated a maximum dose of 3.8
g/kg/d lipid emulsion without lipid clearance problems.
Parental nutrition lasting for 11 months was safe, but
body weight gain remained poor, which might be due tothe DGAT1 deficiency mediating lipid metabolic disorders. Fat-soluble vitamins, such as vitamin A and vitamin D, were maintained in the normal range even when
parenteral nutrition stopped as she was discharged.
Quality of life and prevention of infections should also
be the physician’s concerns.
In summary, we reported a patient with DGAT1 compound heterozygous mutations in the Chinese population who presented delayed chronic diarrhoea. This case
expanded our knowledge of the clinical features of patients with DGAT1 mutations. Paediatricians should be
alert to this disease when infants have delayed intractable diarrhoea with failure to thrive. We had only one
case here, and more studies focusing on the mechanismof lipid metabolism in DGAT1-deficient patients will benecessary in the future.

Supplementary Information
The online version contains supplementary material available at https://doi.
org/10.1186/s12881-020-01164-1.
Additional file 1. Description of immunohistochemical analysis.
Additional file 2. Immunohistochemistry of DGAT1 in the duodenum.
Abbreviations
DGAT1: Diacylglycerol o-acyltransferase 1; TG: Triglyceride;
DAG: Diacylglycerol; PLE: Protein-losing enteropathy;
IHC: Immunohistochemistry; IGF-1: Insulin-like growth factor-1; IGF BP3: Insulin-like growth factor binding protein-3; WAZ: Weight-for-age z-score;
HAZ: Length/height-for-age z-score; WHZ: Weight-for-length z-score;
WES: Whole-exome sequencing
Acknowledgments
We thank Mrs. Lili Yang who is the deputy managing editor of World Journalof Paediatrics for her precious advice. We also thank Mr. Wei Ding from
Running Gene Inc. for his effort on gene analysis.
Authors’ contributions
LX, YL, JL, and JC designed the research. YL and JL conducted the research;
WG performed the histological and immunohistochemical examination of

Xu et al. BMC Medical Genetics(2020) 21:239

the specimen. LX and YL collected the data. LX analyzed the data. JC
checked all of the data. LX was a major contributor in writing themanuscript. JC had primary responsibility for the final content. The authors
offered critical comments, read and approved the final manuscript.
Funding
No funding.
Availability of data and materials
WES data of the proband were deposited in the NCBI Sequence Read
Archive (SRA) database (Project ID: PRJNA673384). All datasets generated oranalysed during the current study are included in this published article andavailable from the corresponding author on reasonable request. Database
analysed in the study included gnomAD (gnomad.broadinstitute.org).

Page 7 of 7

9.

10.
11.

12.
13.

14.

15.
Ethics approval and consent to participate
The Ethics Committee of Children’s Hospital Zhejiang University School of
Medicine approved this study (No.2018-IRB-059 and 2019-IRB-001). All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national researchcommittee and with the 1964 Helsinki declaration and its later amendments
or comparable ethical standards. Written consent was obtained from the parents of the proband for the collection of samples and for DNA sequencing.
Consent for publication
Written informed consent for publication of identifying images or the clinicaldetails was obtained from the parents or legal guardians of any participant
under the age 18.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Present Address: Department of Gastroenterology, Children’s Hospital,
Zhejiang University School of Medicine, National Clinical Research Center forChild Health, No.3333, Binsheng Road, Hangzhou, Zhejiang Province, PR
China. 2Present Address: Department of Pathology, Children’s Hospital,
Zhejiang University School of Medicine, National Clinical Research Center forChild Health, No.3333, Binsheng Road, Hangzhou, Zhejiang Province, PR
China.

16.

17.
18.

19.

20.

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Received: 7 May 2019 Accepted: 4 November 2020

Publisher’s Note
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